Valsartan, also known as (S)-N-(1-Carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)bi phenyl-4-ylmethyl]-amine, has the following structure:
and is marketed as the free acid under the name DIOVAN. DIOVAN is prescribed as oral tablets in dosages of 40 mg, 80 mg, 160 mg and 320 mg of valsartan.
Valsartan and/or its intermediates are disclosed in various references, including: U.S. Pat. Nos. 5,399,578, 5,965,592, 5,260,325, 6,271,375, WO 02/006253, WO 01/082858, WO 99/67231, WO 97/30036, Peter Bühlmayer, et. al., Bioorgan. & Med. Chem. Let., 4(1) 29–34 (1994), Th. Moenius, et. al., J. Labelled Cpd. Radiopharm., 43(13) 1245–1252 (2000), and Qingzhong Jia, et. al., Zhongguo Yiyao Gongye Zazhi, 32(9) 385–387 (2001), all of which are incorporated herein by reference.
Valsartan is an orally active specific angiotensin II antagonist acting on the AT1 receptor subtype. Valsartan is prescribed for the treatment of hypertension. U.S. Pat. No. 6,395,728 is directed to use of valsartan for treatment of diabetes related hypertension. U.S. Pat. Nos. 6,465,502 and 6,485,745 are directed to treatment of lung cancer with valsartan. U.S. Pat. No. 6,294,197 is directed to solid oral dosage forms of valsartan. These patents are incorporated herein by reference.
The present invention relates to the solid state physical properties of valsartan. These properties can be influenced by controlling the conditions under which valsartan is obtained in solid form. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability.
These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a substance. The polymorphic form may give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and can be used to distinguish some polymorphic forms from others. A particular polymorphic form may also give rise to distinct spectroscopic properties that may be detectable by powder X-ray crystallography, solid state 13C NMR spectrometry and infrared spectrometry.
U.S. Pat. No. 5,399,578, incorporated herein by reference, in Example 16, obtains valsartan and discloses: “melting interval 105–115 (from ethyl acetate).”
In the Merck Index (12-th edition, p. 1691, valsartan n. 10051), valsartan is described as “crystals from diisopropyl ether, mp 116–117° C.” The Merck Index may be reciting the product of example 37 of EP 0 443 983, which is in German. The product is not otherwise characterized by the Merck Index.
In J. of Labeled compounds and radiopharmaceuticals 2000, 43, 1245–1252 on page 1249 (synthesis of [14C2]valsartan 2), there is a description of the preparation of valsartan by crystallization from a 1:1 mixture of ethyl-acetate and Hexane. Repetition of this procedure led to a sample with X-Ray powder diffraction pattern as depicted in FIG. 1 (bottom pattern). The pattern in FIG. 1 shows a diffuse X-Ray diffraction, which indicates presence of an amorphous material.
WO 02/06253 also discloses amorphous form of valsartan: “The X-ray diffraction diagram consists essentially of a very broad, diffuse X-ray diffraction; the free acid is therefore characterized as almost amorphous under X-ray. The melting point linked with the measured melting enthalpy of 12 kJ/mol [approximately 28 j/g] unequivocally confirm the existence of a considerable residual arrangement in the particles or structural domains for the free acid valsartan. There is a need for more stable, e.g. crystalline forms of valsartan.” The WO 02/06253 then goes on to disclose salts of valsartan in crystalline form.
There is a need in the art for crystalline valsartan in the free acid form. There is also a need in the art for purely amorphous valsartan, which does not undergo “a considerable residual arrangement in the particles or structural domains.” There is also a need in the art for additional processes for preparation of amorphous form.